The extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) is a positive regulator of cell proliferation often upregulated in cancer. Its C. elegans ortholog MPK-1 stimulates germline stem cell (GSC) proliferation non-autonomously, from the intestine or somatic gonad. How MPK-1 can perform this task from either of these two tissues however remains unclear. We reasoned that somatic MPK-1 activity could lead to the generation of pro-proliferative small molecules that could transfer from the intestine and/or somatic gonad to the germline. Here, in support of this hypothesis, we demonstrate that a significant fraction of the small membrane-impermeable fluorescent molecule, 5-carboxyfluorescein (5-CF), transfers to the germline after its microinjection in the animal's intestine. The larger part of this transfer targets oocytes and requires the germline RME-2 yolk receptor. A minor quantity of the dye is however distributed independently from RME-2 and more widely in the animal, including the distal germline, gonadal sheath, coelomocytes and hypodermis. We further show that the intestine-to-germline transfer efficiency of this RME-2 independent fraction does not vary together with GSC proliferation rates or MPK-1 activity. Therefore, if germline proliferation was influenced by small membrane-impermeable molecules generated in the intestine, it is unlikely that proliferation would be regulated at the level of molecule transfer rate. Finally, we show that conversely, a similar fraction of germline injected 5-CF transfers to the intestine, demonstrating transfer bidirectionality. Altogether, our results establish the possibility of an intestine-to-germline signaling axis mediated by small membrane-impermeable molecules that could promote GSC proliferation cell non-autonomously downstream of MPK-1 activity.

中文翻译：

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秀丽隐杆线虫肠道和种系之间膜不渗透小分子的双向转移。


细胞外信号调节激酶/丝裂原活化蛋白激酶 （ERK/MAPK） 是细胞增殖的正调节因子，通常在癌症中上调。其秀丽隐杆线虫直系同源物 MPK-1 非自主刺激来自肠道或体细胞性腺的种系干细胞 （GSC） 增殖。然而，MPK-1 如何从这两个组织中的任何一个执行这项任务仍不清楚。我们推断，体细胞 MPK-1 活性可能导致促增殖小分子的产生，这些小分子可以从肠道和/或体细胞性腺转移到种系。在这里，为了支持这一假设，我们证明了很大一部分膜不渗透性小荧光分子 5-羧基荧光素 （5-CF） 在动物肠道显微注射后转移到种系中。这种转移的大部分以卵母细胞为靶点，需要种系 RME-2 卵黄受体。然而，少量染料独立于 RME-2 分布，并且在动物中分布更广泛，包括远端种系、性腺鞘、体腔细胞和皮下组织。我们进一步表明，这种 RME-2 非依赖性部分的肠道到种系转移效率不随 GSC 增殖速率或 MPK-1 活性而变化。因此，如果种系增殖受到肠道中产生的不透膜小分子的影响，则不太可能在分子转移速率水平上调节增殖。最后，我们表明相反，相反，注射的 5-CF 的相似部分会转移到肠道，证明转移双向性。 总而言之，我们的结果确定了由膜不渗透性小分子介导的肠道到种系信号轴的可能性，该分子可以促进 GSC 增殖细胞非自主地位于 MPK-1 活性的下游。